Encapsulation
encapsulation
Ex vivo gene therapy for epilepsy. Seizure-suppressant and neuroprotective effects of encapsulated GDNF-producing cells
A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the patients. Thus, developing more targeted and effective treatment strategies is highly warranted. Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the brain. We have developed an implantable cell encapsulation system that delivers high and consistent levels of neurotrophic molecules directly to a specific brain region. The potential of this approach has been tested by delivering glial cell line-derived neurotrophic factor (GDNF) to the hippocampus of epileptic rats. In vivo studies demonstrated that these intrahippocampal implants continue to secrete GDNF and produce high hippocampal GDNF tissue levels in a long-lasting manner. Identical implants rapidly and greatly reduced seizure frequency in the pilocarpine model. This effect increased in magnitude over 3 months, ultimately leading to a reduction of spontaneous seizures by more than 90%. Importantly, these effects were accompanied by improvements in cognition and anxiety, and by the normalization of many histological alterations that are associated with chronic epilepsy. In addition, the antiseizure effect persisted even after device removal. Finally, by establishing a unilateral epileptic focus using the intrahippocampal kainate model, we found that delivery of GDNF exclusively within the focus suppressed already established spontaneous recurrent seizures. Together, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner. These findings may form the basis for clinical translation of this approach.
Adhering, wrapping, and bursting of lipid bilayer membranes: understanding effects of membrane-binding particles and polymers
Proteins and membranes form remarkably complex structures that are key to intracellular compartmentalization, cargo transport, and cell morphology. Despite this wealth of examples in living systems, we still lack design principles for controlling membrane morphology in synthetic systems. With experiments and simulations, we show that even the simple case of spherical or rod-shaped nanoparticles binding to lipid-bilayer membrane vesicles results in a remarkably rich set of morphologies that can be reliably controlled via the particle binding energy. When the binding energy is weak relative to a characteristic membrane-bending energy, vesicles adhere to one another and form a soft solid gel, which is a useful platform for controlled release. With larger binding energy, a transition from partial to complete wrapping of the nanoparticles causes a remarkable vesicle destruction process culminating in rupture, nanoparticle-membrane tubules, and vesicle inversion. We have explored the behavior across a wide range of parameter space. These findings help unify the wide range of effects observed when vesicles or cells are exposed to nanoparticles. They also show how they open the door to a new class of vesicle-based, closed-cell gels that are more than 99% water and can encapsulate and release on demand. I will discuss how triggering membrane remodeling could lead to shape-responsive systems in the future.